Naphthothiazolone derivatives active on the D3 dopaminergic receptor

ABSTRACT

A compound of Formula (I) ##STR1## or a pharmaceutically acceptable salt thereof, wherein n is an integer between 2 and 6 and R 1  is a methyl group or a group ##STR2## wherein R 2 , R 3  and R 4  are independently hydrogen, hydroxy, methoxy, methylsulfonyl, or one of R 2 , R 3  and R 4  together with another one of the three substituents forms a --O--CH 2  --O-- bridge. The asterisk marks an asymmetric carbon atom.

This application is a 371 of PCT/EP98/03560 filed Jun. 12, 1998.

The present invention relates to 4,5,6,7-tetrahydro-naphthothiazolonederivatives selectively active on the D₃ dopaminergic receptor.

The D₃ dopaminergic receptor was cloned for the first time by Sokoloffet al. (Nature. 347. 146. 1990), and is abundant in the cerebral areasconnected to the emotional and cognitive functions.

The patent application WO 96/23760 (in the name of Pharmacia & Upjohn)describes 2-aminoindanes with selective activity for the D₃ receptor.

The D₃ -antagonists are said to have a potential use as antipsychotics.e.g. in the therapy of schizophrenia, schizo-emotional diseases,psychotic depression, manias. The pathologies which may be treated withthe D₃ -receptor agonists include dyskinesia, such as Parkinson'sdisease, neuroleptic parkinsonism and late dyskinesia, and alsodepression, anxiety, memory failure, sexual disorders, drug addiction(e.g. from cocaine).

The patent application EP 0 186 087 (in the name of Karl Thomae GmbH)discloses tetrahydrobenzothiazoies N-substituted on both the ringsuseful as D₂ and D₃ receptor agonists, and thus useful in the treatmentof schizophrenia and Parkinson's disease One of these compounds,2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole, is furtherclaimed in the patent application WO 96/18395 (in the name ofUp-john/Boehringer Ingelheim) as endowed with neuroprotective effect.

We have now found a new class of compounds endowed with selectiveactivity on the D₃ doparninergic receptors as antagonists, agonists orpartial agonists.

Therefore the present invention relates to compounds of formula I##STR3## wherein n is an integer comprised between 2 and 6. R₁ is amethyl group or a group ##STR4## wherein R₂, R₃ and R₄ are independentlyhydrogen, hydroxy, methoxy, methylsulfonyl, or one of R₂, R₃ and R₄together with another one of the three substituents forms a --O--CH₂--O-- bridge;

the asterisk marks an asymmetric carbon atom;

and the pharmaceutically acceptable salts thereof.

The compounds of formula I have at least an asymmetric centre, marked byan asterisk, and may therefore be in form of stereoisomers.

Object of the present inventions are the compounds of formula I in formof stereoisomeric mixture and also as single stereoisomers.

The compounds of formula I are active on the D₃ dopamineraic receptorsalso by oral route. They are therapeutically useful in the treatment ofpsychotic diseases, such as schizophrenia, dyskinesia, such asParkinson's disease, of depression, anxiety, memory diseases, sexualdisorders and drug addiction.

Preferred compounds of formula I are the ones wherein the carbon atommarked by an asterisk has the S configuration.

Pharmaceutically acceptable salts of the compounds of formula I aresalts with organic and inorganic acids such as, e.g., hydrochloric,hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, acetic, benzoic,maleic, fumaric, succinic, citric, aspartic, methansulfonic and3,7-di-t.butylnaphthalen-1,5-disulfonic (dibudinic acid).

The preparation of the compounds of formula I is effected according tomethods known by the skilled in the art. For example, a compound formulaII ##STR5## or a salt thereof is duly protected on the amino group, forexample with diterbutylcarbonate, phthalic anhydride or trifluoroaceticanhydride; the hydroxy group is then turned into apolyfluoroalkylsultonyioxy group (R_(f) SO₂ O--) such as, for example,trifluoromethylsulfonyloxy, thereby yielding a compound of formula III##STR6## wherein R_(f) is a lower polyfluoroalkiyl group and PG aprotecting group, which is nitrated for example with nitric acid orother nitrating agzents such as ammonium nitrate/trifluoroaceticanhydride or nitroniurn tetrafluoroborane, to give a compound of formulaIV ##STR7## wherein R_(f) and PG are as defined above. The nitro groupof the compound of formula IV is reduced to amino by hydrogenation inthe presence of a catalyst made of a metal such as palladium, platinum,nickel, rhodium and ruthenium; in the meantime thepolfluoroalkylsulfonyioxy group is reduced, thus obtaining a compound offormula V ##STR8## wherein PG is as defined above, which is reacted witha thiocyanate such as, for example, ammonium or alkali metalthiocyanate, in acidic environment to give a compound of formula VI##STR9## wherein PG is as defined above. This compound is cyclized to anaminothiazole derivative by heating in the presence of thionyl chlorideor bromine in chloroform, and then turned in the equivalent diazoniumsalt applying known techniques. The diazonium salt is turned in thecompound of formula VII ##STR10## wherein PG is as defined above, bytreatment with copper(I)chloride. Alternatively, the compound of formulaVII may be directly obtained from the aminothiazole compound bytreatment with copper(II)chloride and t-butylnitrite. The compound offormula VII is reacted with sodium methylate and then the amino group isdeprotected to give a compound of formula VIII ##STR11## which isreacted with propionic aldehyde in the presence of sodiumcyanoborohydride or under other conditions for reductive ammination.

The compound of formula IX is reacted under dehydrating conditions withan acid of formula X ##STR12## wherein n is as defined above and R₆ ishydrogen or a group ##STR13## wherein R₂, R₃ and R₄ are as definedabove, or with a reactive derivative thereof such as an acyl halide or amixed anhydride which may also be prepared in situ in an inert solventin the presence of a base such as an alkali carbonate or bicarbonate ora tertiary amine, to give an intermediate of formula XI ##STR14##wherein n and R₆ are as defined above, which is treated withhydrochloric acid in hot tetrahydrofiran and subsequently reduced on allthe present amido groups by a reducing agrent such borane or boranecomplexes, for example, with methylsulfide or lithium aluminium hydride,to give the compounds of formula I.

A specific alternative relates to the compounds of formula I wherein nis 2 and R₁ is methyl which may be prepared by reacting the compoundofformula VIII above with a double amount of propionic aldehyde underthe just mentioned conditions.

A compound of formula IX is thus obtained ##STR15## wherein R₅ ishydrogen or a propyl group. The treatment of the compound of formula IXwherein R₅ is propyl with hydrochloric acid in dioxane and methanolallows the obtainment of the compounds of formula I wherein R₁ is methyland n=2.

The compounds of formula I in optically active form are obtained byoptical separation or through stereospecific or stereoselectivesynthesis.

The preparation of the salts of the compounds of formula I is carriedout according to conventional methods.

The compounds of formula I are active on the D₃ dopaminergic receptors.The interaction test with other receptorial systems showed that thecompounds of formula I do not notably interact and thus they are endowedwith high specificity (Example 12).

It is apparent that these selectivity and specificity features make thecompounds of formula I particularly suitable for the treatment ofcentral diseases and in the antipsychotic therapy, in that of thedyskinesia, in the treatment of depression, anxiety, memory problems,sexual disorders and drug addiction.

Moreover these compounds may be used as selective markers for the D₃receptors optionally in form of radioligands.

As a consequence in the therapeutical practice the compounds of formulaI may be administered both parenterally and enterally. The therapeuticaldoses usually range between 0.1 mg and 400 mg a day by oral route forsingle administration.

Another object of the present invention are the pharmaceuticalcompositions containing a therapeutically effective amount of thecompounds of formula I or the pharmaceutically acceptable salts thereofin admixture with a suitable carrier.

The pharmaceutical compositions of the invention may be liquid, suitableto the enteral or parenteral administration, and, preferably, solid suchas tablets, capsules, granulates, suitable to the oral administration.

The preparation of the pharmaceutical compositions of the invention maybe carried out according to common techniques.

A further object of the invention relates to diagnostic kit containingone of the compounds of formula I optionally in form of radioligand.

For better illustrating the present invention the following examples arenow provided.

The chromatographic purifications were effected on silica gel columns(230-400 mesh). Unless otherwise specified, the mass spectra wereeffected under the following conditions: chemical ionisation, isobutane,positive ions.

EXAMPLE 1 Synthesis of(S)-7-trifluoroacetylamino-5,6,7,8-tetrahydro-2-naphthyltrifluoromethansulfonate

A suspension of 7-hydroxy-1,2,3,4-tetrahydro-2-naphtylamine hydrobromide(12.2 g; 50 mmoles) (prepared as described in the patent application FR2653765 in the name of Midy) and triethylamine (25 ml; 175 mmoles) inCH₂ Cl₂ (400 ml) and acetonitrile (20 ml), under stirring at roomtemperature, was dropwise added with a solution of trifluoroaceticanhydride (8.3 ml; 57.5 mmoles) in CH₂ Cl₂ (100 ml). After 2 hours waterwas added (200 ml). The organic phase was washed first with a 1Nsolution of HCl (200 ml) then with water (200 ml), anhydrified over Na₂SO₄ and the solvent evaporated under reduced pressure. The crude wasdissolved in acetonitrile (300 ml) The resulting solution wvas addedwith K₂ CO₃ (12.5 g; 90.7 mmoles) and, dropwise, with a solution ofN-phenyltrifluoromethansulfonimide (17 g; 47.6 mmoles) in acetonitrile(100 ml) at room temperature. The mixture was stirred at roomtemperature for 18 hours, then the solvent was evaporated under reducedpressure. The residue was added with ethyl ether (600 ml) and water (300ml). The phases were separated and the organic one washed first with a1N solution of HCl (300 ml) then with water (300 ml), anhydrified overNa₂ SO₄, and the solvent evaporated under reduced pressure. The crudewas purified by silica gel chromatography (eluent petrolatum:ethylacetate=8:2).

There were obtained 16.1 g of(S)-7-triluoroacetylamino-5,6,7,8-tetrahydro-2-naphthyltrifluoromethansulfonate.

¹ H-NMR (200 Mhz, CDCl₃): δ (ppm) 1.75-1.97 (m, 1H); 2.07-2.22 (m, 1H);2.76 (dd, 1); 2.87-2.98 (m, 2H); 3.20 (dd, 1H); 4.20-4.40 (m, 1H); 6.33(bd, 1H); 6.97 (d, 1H); 7.05 (dd, 1H); 7.18 (d, 1H).

Mass: 392 (M+H)⁺.

EXAMPLE 2 Synthesis of(S)4-nitro-7-trifluoroacetylamino-5,6,7,8-tetrahydro-2-naphthyltrifluoromethansulfonate

A solution of (S)-7-trifluoroacetyiamino-5,6,7,8-tetrahydro-2-naphthyltrifluoromethansulfonate (15.8 g; 40.4 mmoles), prepared as described inexample 1, in trifluoroacetic acid (150 ml), under stirring at 0° C.,was dropwise added with 100% HNO₃ (2.1 ml; 52.5 mmoles). At the end ofthe addition the mixture was left to rise to room temperature and after50 minutes poured into water and ice (1200 ml). The formed precipitatewas filtered the dissolved in ethyl ether (600 ml). The organic phasewas washed with water (2×300 ml), anhrdrified over anhydrous Na₂ SO₄ andthe solvent evaporated under reduced pressure. The resulting crude waspurified by silica gel chromatography (eluent petrolatum:ethylacetate=8:2).

There were obtained 9.8 g of(S)-4-nitro-7-trifluoroacerylamino-5,6,7,8-tetrahydro-2-naphthyltrifluoromethansulfonate.

¹ H-NMR (200 MHz, CDCl₃): (ppm) 1.74-1.97(m,1H); 2.15-2.31(m,1H);2.89(dd,1H); 3.12-3.24(m,2H); 3.38(dd,1H); 4.21-4.41(m,1H); 6.38(bd,1H);7.28(d,1H); 7.72(d,1H).

Mass: 437 (M+H)⁺.

EXAMPLE 3 Synthesis of(S)-N-(5-amino-1,2,3,4-tetrahydro-2-napthyl)trifluoroacetamide

A mixture of(S)-4-nitro-7-trifluoroacetylamino-5,6,7,8-tetrahydro-2-naphthyltrifluoromethansulfonate (9.8 g; 22.5 mmoles), prepared as described inexample 2, and triethylamine (8.2 ml; 56.2 mmoles) in methanol (500 ml)was kept under hydrogen pressure (50 psi=3.4 atm) in the presence of 10%Pd/C (5 g) for 1.5 hour at room temperature. After filtering off thecatalyst the mixture was concentrated to dryness under reduced pressure.The residue was dissolved in ethyl acetate (300 ml) and the solutionwashed with water (3×200 ml), anhydrified over anhydrous Na₂ SO₄ and thesolvent evaporated under reduced pressure. The crude was purified bysilica gel chromatography (eluent methylene chloride:methanol=98.2).

There were obtained 4.4 g of(S)-N-(5-amino-1,2,3,4-tetrahydro-2-naphtyl)-trifluoroacetamide.

¹ H-NMR (200 MHz, CDCl₃): δ (ppm) 1.83-2.24(m,2H); 2.58(m,2H);2.71(dd,1H); 3.12(dd,1H); 3.60(bs,2H); 4.22-4.41(m,1H); 6.26(bd,1H);6.55(m,2H); 6.99(m,1H).

Mass (electronic impact): 258 (M+H)⁻.

The product was subsequently turned into the corresponding hydrochlorideby dissolution into ethyl acetate saturated with HCl followed byevaporation of the solvent under reduced pressure.

EXAMPLE 4 Synthesis of(S)-6-trifluoroacetylamino-5,6,7,8-tetrahydro-1-naphthylthiourea

A suspension of(S)-1,2,3,4-tetrahydro-1,5-naphthalendiamine-2-trifluoroacetamidehydrochloride (4.4 g; 14.9 mmoles), prepared as described in example 3,in chlorobenzene (45 ml), under stirring at 50° C., was added with 12NHCl (0.13 ml) and ammonium thiocyanate (2.27 g; 29.9 mmoles). Themixture was heated to 115° C. for 3 hours. After evaporating the solventunder reduced pressure the resulting residue was added with ethylacetate (200 ml) and water (100 ml). The organic phase was washed withwater (100 ml), anhydrified over anhydrous Na₂ SO₄ and concentrated todryness under reduced pressure. The resulting crude was purified bysilica gel chromatography (eluent methylene chloride:methanol=95:5).

There were obtained 3 g of(S)-6-trifluoroacetyiamino-5,6,7,8-tetrahydro-1-naphthylthiourea.

¹ H-NMR (200 MHz, DMSO-d₆): δ (ppm) 1.59-2.08 (m, 2H); 2.61-3.08 (m,4H); 3.91-4.13 (m, 1H); 6.98-7.19 (m, 3H); 9.16 (bs, 1H); 9.49 (bd, 1H).

Mass (thermospray): 318 (M+H)⁻.

EXAMPLE 5 Synthesis of(S)-2-chloro-6-trifluoroacetylamino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazole

A solution or(S)-6-trifluoroacetylamino-5,6,7,8-tetrahydro-1-naphthylthiourea (2.6 g;8.2 mmoles), prepared as described in example 4, in thionyl chloride (4ml) was heated to 60° C. for 1.5 hour. After cooling to 0° C. water wasadded (50 ml) and the mixture heated again to 80° C. for 2 hours, thenbrought to room temperature, alkalinised with 30% ammonia and extractedwith ethyl acetate. The organic phase was washed with water, anhydrifiedover anhydrous Na₂ SO₄ and concentrated to dryness under reducedpressure. The residue was dissolved in ethyl acetate. After adding ethylacetate saturated with HCl a precipitate was obtained, filtered on aporous sect and washed with petrolatum on the filter. The resultingsolid, dried under vacuum at 50° C. overnight, was portionwise added toa suspension of copper(II)chloride (1 g; 7.4 mmoles) and t-butylnitrite(1.1 ml; 9.2 mmoles) in dry acetonitrile (50 ml), under stirring at 60°C. After 25 minutes the reaction mixture was brought to room temperatureand poured into 20% HCl. After extraction with ethyl ether the organicphase was washed first with 2N HCl then with water, anhydrified overanhydrous Na₂ SO₄ and concentrated to dryness under reduced pressure,The resulting crude was purified by silica gel chromatography (eluentpetrolatum:ethyl acetate=8:2).

There were obtained 1.4 g of(S)-2-chloro-6-trifluoroacetyiamino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazole.

¹ H-NMR (200 MHz, CDCl₃): δ (ppm) 1.84-2.07(m, 1H); 2.14-2.31(m, 1H);2.83(dd, 1H); 3.13-3.49(m, 3H); 4.20-4.39 (m, 1H); 6.2 (bd, 1H); 7.12(d, 1H); 7.55 (d, 1H).

Mass (thermospray): 335 (M+H)⁻.

EXAMPLE 6 Synthesis of(S)-2-methoxy-6-amino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazole

Sodium (0.22 g; 9.6 mmoles) was portionwise added to dry CH₃ OH (30 ml),under stirring at room temperature. When the dissolution was completed aportion of(S)-2-chloro-6-trifluoroacetylamino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazole(1.4 g; 4.2 mmoles), prepared as described in example 5, was added andthe mixture refluxed for 5 hours. After cooling to room temperaturewater (2 ml) and a 32% solution of NaOH (0.5 ml) were added and themixture was refluxed again for 2 hours. After evaporation of the solventunder reduced pressure the residue was added with methylene chloride andwater. The phases were separated and the organic one was washed with asaturated solution of NaCl, anhydrified over anhydrous Na₂ SO₄ andconcentrated to dryness under reduced pressure.

There was obtained 0.95 g of(S)-2-methoxy-6-amino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazoie.

¹ H-NMR (200 MHz, CDCl₃): δ (ppm) 1.43 (bs, 2H); 1.51-1.74 (m, 1H);2-2.17 (m, 1H); 2.6 (m, 1H); 2.89-3.4 (m, 4H); 4.16 (s. 3H); 6.93 (d,1H); 7.38 (d, 1H).

Mass (thermospray): 235 (M+H)⁻.

EXAMPLE 7 Synthesis of(S)-2-methoxy-6-dipropylamino-4,5,6,7-tetrahydronaphtho(1,2-d)-thiazole

A solution of(S)-2-methoxy-6-amino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazole (0.1 g;0.42 mmoles), prepared as described in example 6, in CH₃ OH (5 ml),under stirring at room temperature on 3Å molecular sieves, was addedwith sodium acetate (56 mg; 0.68 mmoles), sodium cyanoborohydride (54mg; 0.85 mmoles) and propionic aldehyde (0.09 ml; 1.26 mmoles). After 18hours the reaction mixture was poured into water. After extraction withethyl acetate the organic phase was washed with a saturated solution ofNaCl, anhydrified over Na₂ SO₄ and concentrated to dryness under reducedpressure. The resulting crude was purified by silica gel chromatography(eluent methylene chloride:methanol; 30% ammonia=90:10:0.5).

There were obtained 108 mg of(S)-2-methoxy-6-dipropylamino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazole.

¹ H-NMR (200 MHz, CDCl₃): δ (ppm) 0.89(t,6H); 1.37-1.75(m,5H);2.03-2.18(m,1H); 2.49(m,4H); 2.71-3.09(m,4H); 3.40(m,1H); 4.16(s,3H);6.95(d,1H); 7.37(d,1H).

Mass (thermospray): 319 (M+H)⁻.

EXAMPLE 8 Synthesis of(S)-6-dipropylamino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazol-2(3H)-onehydrochloride (Compound 1)

A solution of(S)-2-methoxy-6-dipropylamino-4,5,6,7-tetrahydronaphtho(1,2-d)-thiazole(0.1 g; 0.31 mmoles), prepared as described in example 7, in methanol (1ml) and dioxane (3 ml) was added with 3 drops of 37% HCl. The mixturewas stirred at room temperature for 6 hours, then the solvents wereevaporated under reduced pressure. There were obtained 107 mg of(S)-6-dipropylamino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazol-2(3H)-onehydrochloride.

¹ H-NMR (200 MHz, D₂ O): δ (ppm) 0.84 (t. 6H); 1.50-2.23 (m, 6H);2.47-3.14 (m, 8H); 3.49-3.66 (m, 1H); 6.81 (d, 1H); 7.10 (d, 1H).

Mass (thermospray): 305 (M+H)⁻.

EXAMPLE 9 Synthesis of(S)-2-methoxy-6-propylamino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazole

A solution of(S)-2-methoxy-6-amino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazole (0.35 g;1.49 mmoles), prepared as described in example 6, in methanol (15 ml),under stirring at room temperature on 3 Å molecular sieves, was addedwith sodium acetate (196 mg; 2.4 mmoles), sodium cyanoborohydride (188mg; 3 mmoles) and propionic aldehyde (0.107 ml; 1.49 mmoles). After 25hours the mixture was evaporated to dryness under reduced pressure andthe resulting residue was added with ethyl acetate and water. The phaseswere separated and the organic one was washed with a saturated solutionof NaCl, anhydrified over anhydrous Na₂ SO₄ and concentrated to drynessunder reduced pressure. The resulting crude was purified by silica gelchromatography (eluent methylene chloride:methanol:30%ammonia=90:10:0.5).

There were obtained 270 mg of(S)-2-methoxy-6-propylamino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazole.

¹ H-NMR (200 MHz, CDCl₃): δ (ppm) 0.93 (t, 3H); 1.43-2.21 (m, 5H);2.57-3.14 (m, 6H); 3.30 (m, 1H); 4.16 (s, 3H); 6.95 (d, 1H); 7.37 (d,1H).

Mass (thermospray): 277 (M+H)⁻.

EXAMPLE 10 Synthesis of(S)-6-N-propyl-N-6-[(4-methylsulfonylohenyl)acetylamino]-1-keto-hexyl-amino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazol-2(3H)-one

A suspension of 6-(4-methylsulfonylphenyl)acetamidohexanoic acid (320mg, 0.95 mmoles) in methylene chloride (5 ml) was added under stirringat room temperature with thionyl chloride (0.082 ml; 1.13 mmoles). After1.5 hour the solvent and the exceeding thionyl chloride were evaporatedunder reduced pressure. The resulting oil was dissolved in methylenechloride (5 ml) and the obtained solution was dropwise added, understirring at room temperature, to a solution of(S)-2-methoxy-6-propylamino-4,5,6,7-tetraihydronaphtho(1,2-d)thiazole(240 mg; 0.87 mmoles), prepared as described in example 9, andtriethylamine (0.38 ml; 2.6 mmoles) in methylene chloride (20 ml). After1 hour the reaction mixture was poured into water and methylenechloride. The organic phase was washed first with a 5% solution of KHCO₃then with water, anhydrified over anhydrous Na₂ SO₄ and concentrated todryness under reduced pressure, the residue was dissolved in THF (15 ml)and the solution was added with 3 drops of 37% HCl. The reaction mixturewas heated to 60° C. for 6 hours, then evaporated to dryness underreduced pressure and the resulting residue was added with methylenechloride and water. The phases were separated and the organic one waswashed with water, anhydrified over anhydrous Na₂ SO₄ and concentratedto dryness under reduced pressure. The obtained crude was purified bysilica gel chromatography (eluent methylene chloride:methanol=9:1).

There were obtained 450 mg of(S)-6-N-propyl-N-6-[(4-methylsulfonylphenyl)acetyl-amino]-1-keto-hexyl-amino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazol-2(3H)-one.

¹ H-NMR (200 MHz, CDCl₃): δ (ppm) 0.90 and 0.93 (2t, 3H); 1.22-2.18 (m,10H); 2.29-2.41 (m, 2H); 2.72-3.36 (m, 8H); 3.02 and 3.04 (2s, 3H); 3.60(s, 2H); 3.89-4.11 and 4.47-4.69 (2m, 1H); 6.25 and 6.39 (2bt, 1H);6.79-6.93 (2d, 1H); 7.09-7.23 (2d, 1H); 7.43-7.90 (m, 4H); 9.83 and 9.90(2bs, 1H).

Mass (thermospray): 572 (M+H)⁻.

EXAMPLE 11 Synthesis of(S)-6-N-propyl-N-6-[2-(4-methylsulfonylphenyl)ethylamino]hexylamino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazol-2(3H)-onedihydrochloride (Compound 2)

A solution of(S)-6-N-propyl-N-6-[(4-methylsulfonylphenyl)acetylamino]-1-keto-hexyl-amino-4,5,6,7-tetrahydronaphtho(1,2-d)thiazol-2(3H)-one(300 mg; 0.52 mmoles), prepared as described in example 10, in dry THF(15 ml) was dropwise added with borane methylsulfide (0.4 ml; 4.2mmoles) under stirring at room temperature. At the end of the additionthe mixture was refluxed for 3 hours. After cooling to 5° C. a solutionof 37% HCl (0.4 ml) in methanol (4 ml) was dropwise added, the mixturewas refluxed again for 3 hours. The crude obtained after evaporation ofthe solvents under reduced pressure was purified by silica gelchromatography (eluent methylene chloride:methanol:50% formicacid=85:15:2). The resulting product was dissolved in absolute ethanoland this solution was brought to neatly acid pH by adding ethyl ethersaturated with HCl. After evaporation under reduced pressure there wereobtained 210 mg of(S)-6-N-propyl-N-6-(2-(4-methylsulfonylphenyl)-ethyl-amino)hexyl-amino-4,5,6,7-tetrahydronaphtho-(1,2-d)-thiazol-2(3H)-onedihydrochloride.

¹ H-NMR (200 MHz, D₂ O): δ (ppm) 0.84 (t, 3H); 1.23-2.26 (m, 12H); 3.07(s, 3H); 2.51-3.23 (m, 14H); 3.56-3.72 (m, 1H); 6.83-7.13 (m, 2H);7.36-7.74 (m, 4H).

Mass (thermospray): 544 (M+H)⁻.

EXAMPLE 12 Test for evaluating the bindings to dopaminergic receptors incell cultures

Chinese hamster ovary cells (CHO) transfected with dopaminergic receptorsubtypes and murine mesencephalic neuronal (NM9D) expressing thedifferent subtypes of such receptors were used. The cell lines weregrown on Petri dishes, in a mixture of DMEM and Ham's F12 medium 1:1supplemented with 10% foetal bovine serum (FBS), penicillin,streptomycin, geneticin (500 μg/ml) and glutamin in a humidified 5% CO₂atmosphere at 37° C. When cells reached confluence they were washed with10 ml of PBS (KCl 2.68 mM, KH₂ PO₄ 1.4 mM, NaCl 0.13 mM and Na₂ HPO₄ 6.4mM) then 5 ml of lysis buffer (Tris-HCl 10 mM and EDTA 5 mM) were addedto each Petri. Cells were scrapped and the solution centrifuged for 20minutes at 48,000 gravity, 4° C. The pellet was suspended in a minimalamount of lysis buffer and homogenised for 15 seconds. The membranesolution was aliquotated in portions of from 1 to 1.5 ml at a proteinconcentration of about 3 mg/ml (measures by a Bio-Rad protein assaybased on the differential change of colour of a dye in response todifferent concentration of protein), placed in plastic tubes, rapidlyfrozen in liquid nitrogen and stored at -80° C. The binding test wasperformed as reported by Billard et al. 1984, Life Sciences, 35.1885-1893. Seabrook et al. 1992, FEBS, 312, 123-126 and Sunahara et al.1991, Nature, 350, 614-619. For saturation experiments [3H]-SCH23390(Amersharm; specific activity=70 Curie/mmole) was used as radioligandfor D₁ receptors, D₅ and [3H]-spiperone (Amersharm; specificactivity=113 Curie/mmole) for D₂, D₃ and D₄ receptors. Saturation curveswere analysed using Ligand® program to have Kd (dissociation constant)and Bmax (number of receptors/mg of protein) (Munson and Rodbar,1980Anal. Biochem., 107, 220-239).

Displacement studies were performed on cell membrane at the followingconditions:

    ______________________________________                                        Recep-            Radioligand                                                 tor   Radioligand Concentration                                                                            Non specific                                     ______________________________________                                        D.sub.1                                                                             [3H]-SCH23390                                                                             0.2 nM     (-)cis-flupenthixol (1 μM)                    D.sub.5                                                                             [3H]-SCH23390                                                                             0.2 nM     (-)cis-flupenthixol (1 μM)                    D.sub.2s                                                                            [3H]-spiperone                                                                            0.1 nM     (+)-butaclamol (1 μM)                         D.sub.3                                                                             [3H]-spiperone                                                                            0.3 nM     (+)-butaclamol (1 μM)                         D.sub.4                                                                             [3H]-spiperone                                                                            0.2 nM     (+)-butaclamol (1 μM)                         ______________________________________                                    

The compounds of the invention were tested at increasing concentrationsfor evaluating their binding to the various receptors, expressed as Ki(affinity constant) obtained through the Cheng and Prusoff equation

The results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                                Receptor binding (Ki nM)                                              Compound  D.sub.1   D.sub.5                                                                              D.sub.2s                                                                              D.sub.3                                                                            D.sub.4                               ______________________________________                                        1         >10.sup.4 >10.sup.4                                                                            n.d.    489  9841                                  2         >10.sup.4 9273   9440    92   >10.sup.4                             ______________________________________                                    

The compounds of formula I show to selectively bind D₃ receptor havingan affinity constant for the remaining tested receptors neatly higher.

What is claimed is:
 1. A compound of formula ##STR16## wherein n is aninteger between 2 and 6; R₁ is a methyl group or a group ##STR17##wherein R₂, R₃ and R₄ are independently hydrogen, hydroxy, methoxy,methylsulfonyl, or one of R₂, R₃ and R₄ together with another one of thethree substituents forms a --O--CH₂ --O-- bridge;the asterisk marks anasymmetric carbon atom; or a pharmaceutically acceptable salt thereof.2. A compound according to claim 1 wherein the carbon atom marked by anasterisk has the S configuration.
 3. A compound according to claim 1 inoptically active form.
 4. A process for preparing a compound accordingto claim 1 comprising the reduction and the subsequent treatment withhydrochloric acid of a compound of formula ##STR18## wherein R₆ ishydrogen or a group ##STR19## and n, R₂, R₃ and R₄ are as defined inclaim
 1. 5. A pharmaceutical composition containing a therapeuticallyeffective amount of a compound according to claim 1 in admixture with asuitable carrier.
 6. A pharmaceutical composition according to claim 5for the treatment of psychotic disease, of dyskinesia, of depression,anxiety, memory problems, sexual disorders and drug addiction.
 7. Adiagnostic kit containing a compound according to claim
 1. 8. Adiagnostic kit containing a compound according to claim 1 in the form ofa radioligand.
 9. A method of treating a disorder associated with a D₃receptor in a patient in need thereof, the method comprisingadministering to the patient a disorder treating effective amount of acompound according to claim
 1. 10. A method of selectively binding a D₃receptor, the method comprisingproviding an in vitro cell sample havingD₃ receptors; and adding a compound according to claim 1 to the sampleto selectively bind the D₃ receptors.
 11. The method according to claim10 wherein the compound is in the form of a radioligand.